Abstract The long - term objective of the proposal is to investigate the efficacy of neuropeptide Y receptor 2 (Y2R) antagonists as newer and effective anti-angiogenic drugs in advanced colon cancer. Recent reports from the clinics indicate increased resistance to the currently used anti-VEGF-A drugs, the most common anti- angiogenic agents approved for the treatment of advanced colon cancer patients. This thus necessitates identification of newer and effective anti-angiogenic drugs targeting other proangiogenic molecules in colon cancer. Our preliminary results indicate significantly higher expression of neuropeptide Y (NPY) in malignant colon tumor tissues collected from advanced colon cancer patients and orthotopic human colon cancer in mice. In addition, we also observed increased expression of Y2R in tumor endothelial cells (TEC) in these patients and in orthotopic tumors. Because our preliminary data also indicate that NPY can stimulate the proangiogenic functions of normal colon endothelial cells and as significantly increased angiogenesis was observed in colon cancer, it is therefore possible that NPY regulates angiogenesis in malignant colon tumors. The experiments here are designed to investigate the regulatory role of NPY in colon cancer angiogenesis and the effects of targeting Y2R in TEC in inhibiting tumor angiogenesis and thereby growth of colon cancer. Aim I will investigate the effects of inhibition of Y2R by specific antagonists either alone or in combination with standard anti-cancer agents, on angiogenesis and growth of metastatic colon cancer in a preclinical murine models simulating advanced colon cancer and Aim 2 will elucidate the molecular signaling pathways by which NPY regulates tumor angiogenesis. Finally, the knowledge generated from this proposal may not only identify a novel regulator of malignant colon tumor angiogenesis, but can also suggest a newer and an effective therapy for the treatment of advanced colon cancer patients.